Radiation injury is damage to tissues caused by exposure to radiation. Herein, “radiation” refers to ionizing radiation caused by high-energy electromagnetic waves (X-rays, gamma rays) or particles (alpha particles, beta particles, neutrons). Such radiation is emitted by radioactive substances (radioisotopes), such as uranium, radon, and plutonium. Such radiation is also produced by man-made sources, such as x-ray and radiation therapy machines. Radiation dose is measured in several different units, but all relate to the amount of energy deposited. The units include the roentgen (R), the gray (Gy), and the sievert (Sv). The sievert and gray are similar, except the sievert takes into account the biologic effects of different types of radiation. The two main types of radiation exposure are irradiation and contamination. Many radiation accidents expose a person to both.
Irradiation is exposure to radiation waves that pass directly through the body from outside the body. Irradiation can make a person sick immediately (acute radiation illness). Additionally, irradiation, particularly in high doses, can damage a person's genetic material (DNA), causing chronic (delayed) disorders, such as cancer and birth defects. However, irradiation does not make the person or his tissues radioactive. Contamination is contact with and retention of radioactive material, typically in the form of a dust or liquid. The radioactive material may stay on the skin, where it can fall or be rubbed off, contaminating other people and objects. The material also may be absorbed by the body through the lungs, digestive tract, or breaks in the skin. The absorbed material is transported to various sites in the body, such as the bone marrow, where it continues to release radiation. This internalized radiation does not only cause acute radiation illness, such as internal bleeding, but may produce chronic disorders, such as cancer, as well.
People are constantly exposed to low levels of natural radiation (background radiation). Radiation comes from outer space (cosmic radiation), although much of it is blocked by the earth's atmosphere. Exposure to cosmic radiation is greater for people living or working at high radioactive elements, particularly radon gas, which are also present in many rocks and minerals. These elements end up in a variety of substances, including food and construction materials. In addition, people are exposed to radiation from man-made sources, including the environmental radiation that results from nuclear weapons testing and radiation from various medical tests and treatments. The average person receives a total of about three to four mSv (1 mSv= 1/1000 Sv) per year from natural radiation and man-made sources. People who work with radioactive materials and with x-ray sources are at risk of exposure to higher levels of radiation. People who are receiving radiation treatments for cancer may receive very high levels of radiation. Nuclear weapons release massive amounts of radiation. These weapons have not been used against people since 1945. However, a number of nations now possess nuclear weapons, and several terrorist groups have also tried to obtain them, raising the possibility that these weapons could once again be used.
The damaging effects of radiation depend on several factors, including the amount (dose) and duration of exposure. A single, rapid dose of radiation to the entire body can be fatal, but the same total dose given over a period of weeks or months may have much less effect. For a given dose, genetic damage is more likely with rapid exposure. The effects of radiation also depend on how much of the body is exposed. For example, more than 6 Gy generally causes death when the radiation is distributed over the entire body; however, when concentrated in a small area, as in radiation therapy for cancer, three or four times this amount can be given without serious harm to the subject as a whole.
The distribution of radiation is also important, because certain parts of the body are more sensitive to radiation. Organs and tissues in which cells are multiplying quickly, such as the intestines and bone marrow, are harmed more easily by radiation than those in which cells multiply more slowly, such as muscles and tendons. The genetic material of sperm and egg cells can be damaged by radiation. During radiation therapy for cancer, therefore, every attempt is made to shield the more vulnerable parts of the body from radiation so that high doses can be delivered primarily to the cancer.
Radiation exposure produces two types of injury: acute (immediate) and chronic (delayed). Acute radiation injury triggers inflammation through vascular endothelial damage leading to leaking vessels. A vascular response and a cellular response follow. Ionizing radiation depresses immunity and damages intestinal epithelium, both of which promote microbial translocation from the intestines.
Radiation therapy for cancer mainly produces symptoms in the part of the body that receives radiation. For example, in radiation therapy for rectal cancer, abdominal cramping and diarrhea are common because of the effects of radiation on the small intestine.
The search for non-toxic radioprotective agents that can protect normal tissue against radiation damage began soon after World War II. Extensive radiobiological research yielded numerous agents which, when given before radiation exposure, protected animals (primarily rodents) against radiation injuries (K. N. Prasad, Handbook of Radiobiology, 2nd ed. Boca Raton, Fla.; CRC Press, 1995). From these studies, it became clear that agents, which scavenge free radicals and/or cause hypoxia, may be of radioprotective value. Unfortunately, most of these compounds at radioprotective doses were found to be toxic to humans. With the decreased risk of nuclear confrontation experienced during the evolution of the cold war and later, the interest in the study of radioprotective agents markedly decreased. Due to rapid growth of X-ray-based diagnostic equipments and increased use of radiological procedures in the early diagnosis of disease, concerns are being raised about increased frequency of somatic and heritable mutations that can enhance the risk of gene-linked diseases in present and future generations. Therefore, it has become imperative that normal tissues be protected against potential radiation damage no matter how small that damage might be.
Commonly, radioprotective agents are defined as compounds that are administered before exposure to ionizing radiation to reduce its damaging effects, including radiation-induced lethality (H. B. Stone et al., “Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries,” Report of an NCI Workshop, Dec. 3-4, 2003, Radiat. Res. 162:711-728). They have applications in radiological terrorism, military scenarios, clinical oncology, space travel, radiation site cleanup. R. H. Johnson, “Dealing with the terror of nuclear terrorism,” Health Phys. 87:S3-7; F. A. J. Mettler, G. L. Voelz, “Major radiation exposure—what to expect and how to respond,” N. Engl. J. Med. 346:1554-1561 (2001); C. K. Nair, D. K. Parida, T. Nomura, “Radioprotectors in radiotherapy,” J. Radiat. Res. (Tokyo) 42:21-37; J. K. Waselenko, T. J. MacVittie, W. F. Blakely, N. Pesik, A. L. Wiley, W. E. Dickerson, H. Tsu, D. L. Confer, C. N. Coleman, T. Seed, P. Lowry, J. O. Armitage, N. Dainiak, “Medical management of the acute radiation syndrome: Recommendations of the Strategic National Stockpile Radiation Working Group,” Ann. Intern. Med. 140:1037-1051. Recently, the U.S. Office of Science and Technology Policy and the Homeland Security Council have made the development of new radioprotectors a top research priority. Although synthetic radioprotectors, such as the aminothiols, have yielded the highest protective factors, typically they are more toxic than naturally occurring protectors. In general, the best radioprotective agents have also been reported to result in the highest behavioral toxicity.
In a military radiation scenario, the effective mitigation of radiation-induced health consequences and performance-degrading effects can reduce the casualty load at medical treatment facilities, sustain a more effective operational force after a radiation exposure event, allow commanders to conduct operations in radiation field environments with reduced risk of decremented performance due to acute tissue injury, and reduce the negative psychological impact on personnel tasked to operate in contaminated environments. The ideal radioprotectant would be nontoxic, would not degrade performance, and would be effective after a single administration, particularly when expedited entry is required into an area with potential external radiation hazards.
In a paper (Landauer et al., NATO RTG-099 2005) presented at the NATO Human Factors and Medicine Panel Research Task Group 099 “Radiation Bioeffects and Countermeasures” meeting, held in Bethesda, Md., USA, Jun. 21-23, 2005, and published in AFRRI CD 05-2, genisteine was forwarded as giving prevention of gamma radiation-induced mortality in mice, having a “Dose reduction Factor” (DRF) at the best dose (200 mg/kg; which resulted in the highest survival rate when administered to mice 24 hours before irradiation) of 1.16. When given at one hour prior to whole body irradiation (WBI), no radioprotection was observed. Other studies describing the radiation protection activity of a drug code-named ON-01210 that were presented at the 51st Radiation Research Society (April, 2004), show that this particular drug ON-01210 (like other drugs that are currently under investigation for radiation exposure) is protective only if it is given pre-radiation exposure. This particular drug has a sulfhydryl component (4-carboxystyrl-4-chlorobenzylsulfone) that works as an antioxidant, scavenging the free radicals that are generated as the radiation damages the cells.
Also, as stated in the annual report to the Congress of the U.S. Department of Defense (Mar. 2005; medchembio.amedd.army.mil/docs/CBDP_Report_To_Congress. pdf), currently, there are no commercially available non-toxic pharmaceutical agents or diagnostic capabilities suitable for use in military operational environments. An aminothiol compound, amifostine, is FDA approved for use in patients receiving chemotherapy or radiation therapy, but its performance-degrading toxic side effects prohibit its use in a fit fighting force, and its intravenous route of administration requires that medical professionals be available. Other pharmacologic agents, such as hematopoietic cytokines for treating bone marrow injury, may be used off-label on a case-by-case basis by an individual physician, but regulatory restrictions for such use make it impractical for treating large numbers of casualties during military operations. Antibiotics are commonly used to treat the infectious sequelae of radiological injuries, but they must be appropriately selected to effectively treat exogenous and endogenous systemic infections while only little affecting beneficial intestinal anaerobic bacteria.
In addressing the issue of currently limited medical countermeasure alternatives, a novel compound, 5-androstenediol (5-AED; Whitnall et al., Experimental Biology and Medicine 226:625-627 (2001)), has been under study at the Armed Forces Radiobiology Research Institute (AFRRI). Again, the compound showed good efficacy as a radioprotectant when administered prior to irradiation challenge in a mouse model. Improvements in survival were observed when AED was administered by sc injection between 24 hours before and 2 hours after gamma-irradiation of mice. A dose reduction factor of 1.3 was calculated from probit survival curves for the administration prior to WBI. Protection was observed in both male and female mice, with and without subsequent inoculation with lethal doses of Klebsiella pneumoniae. No protection was observed with a number of other steroids: dehydroepiandrosterone (DHEA), 5-androstene-3B,7B, 17B-triol (AET), androstenedione, or estradiol. However, expanded studies in a nonhuman primate (NHP) model during the past year in preparation for the IND application proved 5-AED is far less effective than in the mouse model when administered as a radioprotectant but yielded good efficacy in the NHP model when administered therapeutically in serial doses shortly following irradiation.
Acute Radiation Illness
Acute radiation illness generally occurs in people whose entire body has been exposed to radiation. Acute radiation illness progresses through several stages, beginning with early symptoms (prodrome) and followed by a symptom-free period (latent stage). Various syndromes (patterns of symptoms) follow, depending on the amount of radiation the person received. The greater the amount of radiation, the more severe the symptoms and the quicker the progression from the early symptoms to the actual syndrome. The symptoms and time course are consistent from person to person for a given amount of radiation exposure. Doctors can predict a person's radiation exposure from the timing and nature of the symptoms. Doctors divide acute radiation syndromes into three groups based on the main organ system affected, although there is overlap among these groups.
The hematopoietic syndrome is caused by the effects of radiation on the bone marrow, spleen, and lymph nodes—the primary sites of blood cell production (hematopoiesis). Loss of appetite (anorexia), lethargy, nausea, and vomiting begin 2 to 12 hours after exposure to 2 Gy or more of radiation. These symptoms resolve within 24 to 36 hours after exposure, and the person feels well for a week or more. During this symptom-free period, the blood-producing cells in the bone marrow, spleen, and lymph nodes begin to waste away and are not replaced, leading to a severe shortage of white blood cells, followed by a shortage of platelets and then red blood cells. The shortage of white blood cells can lead to severe infections. The shortage of platelets may cause uncontrolled bleeding. The shortage of red blood cells (anemia) causes fatigue, weakness, paleness, and difficulty breathing during physical exertion. After four to five weeks, if the person survives, blood cells begin to be produced once more, but the person feels weak and tired for months.
The gastrointestinal syndrome is due to the effects of radiation on the cells lining the digestive tract. Severe nausea, vomiting, and diarrhea begin 2 to 12 hours after exposure to 4 Gy or more of radiation. The symptoms may lead to severe dehydration, but they resolve after two days. During the next four or five days, the person feels well, but the cells lining the digestive tract, which normally act as a protective barrier, die and are shed. After this time, severe diarrhea—often bloody—returns, once more resulting in dehydration. Bacteria from the digestive tract invade the body, producing severe infections. People who have received this much radiation also likely develop the hematopoietic syndrome, which results in bleeding and infection and increases their risk of death.
The cerebrovascular (brain) syndrome occurs when the total dose of radiation exceeds 20 to 30 Gy. A person rapidly develops confusion, nausea, vomiting, bloody diarrhea, and shock. Within hours, blood pressure falls, accompanied by seizures and coma. The cerebrovascular syndrome is considered always fatal.
Chronic Effects of Radiation
Chronic effects of radiation result from damage to the genetic material in dividing cells. These alterations may cause abnormalities of cell growth, such as cancer. In severely irradiated animals, damage to reproductive cells has been shown to lead to defective offspring (birth defects). However, little deformities resulting from irradiation have been observed in the offspring of survivors of the nuclear blasts in Japan. It may be that radiation exposure below a certain (unknown) level does not alter genetic material enough to cause birth defects.
Irradiation injury is suspected when a person becomes ill after receiving radiation therapy or being exposed to radiation in an accident. No specific tests are available to diagnose the condition, although certain tests may be used to detect infection, low blood count, or organ malfunction. To determine the severity of radiation exposure, doctors measure the number of lymphocytes (a type of white blood cell) in the blood. The lower the lymphocyte count 48 hours after exposure, the worse the radiation exposure.
Radioactive contamination, unlike irradiation, can be determined by surveying a person's body with a Geiger counter, a device that detects radiation. Swabs from the nose, throat, and any wounds also are checked for radioactivity.
The outcome of radiation injury depends on the dose, dose rate (how quickly the exposure has occurred), and distribution over the body as well as on the person's underlying state of health. In general, most people who have received more than 6 Gy of WBI die of gastrointestinal syndrome. Because doctors are unlikely to know the exact amount of radiation a person has received, they usually judge outcome by the person's symptoms. The cerebrovascular syndrome is fatal within hours to a few days. The gastrointestinal syndrome generally is fatal within three to ten days, although some people survive for a few weeks. Many people who receive proper medical care survive the hematopoietic syndrome, depending on their total amount of radiation; those who do not survive typically die after 8 to 50 days.
Irradiation has no current emergency treatment, but doctors closely monitor the person for the development of the various syndromes and treat the symptoms as they arise. Also, and unfortunately, very few medical products exist to counter the variety of acute and long-term toxicities that can result from nuclear or radiological attacks. Contamination requires immediate removal of the radioactive material to prevent it from being taken up by the body. Skin contaminated by radioactive materials should be scrubbed immediately with large amounts of soap and water or with a solution designed for this purpose, when available. Small puncture wounds should be cleaned vigorously to remove all radioactive particles, even though scrubbing may cause pain. Contaminated hair is clipped off, not shaved—shaving may abrade the skin and allow contamination to enter the body. Scrubbing continues until the Geiger counter shows that the radioactivity is gone. If a person has recently swallowed radioactive material, vomiting is induced. Some radioactive materials have specific antidotes that can prevent absorption of swallowed material. Most such antidotes are given only to people exposed to significant radioactive contamination, such as from a major reactor accident or nuclear explosion. Potassium iodide prevents the thyroid gland from absorbing radioactive iodine and lowers the risk of thyroid cancer. Other drugs, such as diethylene triamine pentaacetic acid (DTPA), ethylenediamine tetraacetic acid (EDTA), and penicillamine, can be given intravenously to remove certain radioactive elements after they have been absorbed.
When contamination is not suspected, nausea and vomiting can be reduced by taking drugs to prevent vomiting (anti-emetics); such drugs are routinely given to people undergoing radiation therapy. Dehydration is treated with fluids given intravenously.
People with the gastrointestinal or hematopoietic syndrome are kept isolated so that they do not contact infectious microorganisms. Blood transfusions and injections of growth factors (such as erythropoietin and colony-stimulating factor) that stimulate blood cell production are given to decrease bleeding and increase blood counts. If the bone marrow is severely damaged, these growth factors are ineffective, and sometimes bone marrow transplantation is performed, although the success rate is low.
People with the gastrointestinal syndrome require anti-emetics, fluids given intravenously, and sedatives. Some people may be able to eat a bland diet. Antibiotics, such as neomycin, are given to kill bacteria in the intestine that may invade the body. Antibiotics, as well as antifungal and antiviral drugs, are given intravenously when necessary. Treatment for the cerebrovascular syndrome is geared toward providing comfort by relieving pain, anxiety, and breathing difficulties. Drugs are given to control seizures.
People with chronic effects of radiation or disorders caused by radiation therapy receive treatment directed at their symptoms. Sores or ulcers can be removed or repaired surgically and can be helped to heal with the use of high-pressure (hyperbaric) oxygen therapy. Radiation-induced leukemia is treated with chemotherapy. Blood cells can be replaced through transfusions. No treatment can reverse sterility, but low levels of sex hormones as a result of abnormal ovarian and testicular functioning can be treated with replacement hormones. Investigators are currently exploring ways to prevent or reduce radiation-induced normal tissue injury using cytokines, growth factors, and various other therapies. Amifostine or pilocarpine-HCl have been shown to decrease the severity of dry mouth (xerostomia) in people with head and neck cancer treated with radiation therapy.
Clinical and experimental studies of the acute and late effects of radiation on cells have enhanced our knowledge of radiotherapy and have led to the optimization of radiation treatment schedules and to more precise modes of radiation delivery. However, as both normal and cancerous tissues have similar response to radiation exposure, radiation-induced injury on normal tissues may present either during, or after the completion of, the radiotherapy treatment. Studies on both NSAIDs and prostaglandins have indeed shown some evidence of radioprotection. Both have the potential to increase the survival of cells but by entirely different mechanisms. Studies of cell kinetics reveal that cells in the mitotic (M) and late G2 phases of the cell cycle are generally most sensitive to radiation compared with cells in the early S and G1/G0 phases. Furthermore, radiation leads to a mitotic delay in the cell cycle. Thus, chemical agents that either limit the proportion of cells in the M and G2 phases of the cell cycle or enhance rapid cell growth could, in principle, be exploited for their potential use as radioprotectors to normal tissue during irradiation.
NSAIDs have been shown to exert anti-cancer effects by causing cell-cycle arrest, shifting cells towards a quiescence state (G0/G1). The same mechanism of action was observed in radioprotection of normal tissues. An increase in arachidonic acid concentrations after exposure to NSAIDs also leads to the production of an apoptosis-inducer ceramide. NSAIDs also elevate the level of superoxide dismutase in cells. Activation of heat shock proteins by NSAIDs increases cell survival by alteration of cytokine expression. A role for NSAIDs with respect to inhibition of cellular proliferation possibly by an anti-angiogenesis mechanism has also been suggested. Several in vivo studies have provided evidence suggesting that NSAIDs may protect normal tissues from radiation injury.
Prostaglandins do not regulate the cell cycle, but they do have a variety of effects on cell growth and differentiation. PGE2 mediates angiogenesis, increasing the supply of oxygen and nutrients essential for cellular survival and growth. Accordingly, PGE2 at sufficiently high plasma concentrations may enhance cellular survival by inhibiting pro-inflammatory cytokines such as TNF-α and IL-1β. Thus, PGE2 acts as a modulator, rather than a mediator, of inflammation. Prospective studies have suggested the potential use of misoprostol, a PGE1 analogue, before irradiation, in prevention of radiation-induced side effects. The current understanding of the pharmacology of NSAIDs and prostaglandins shows some potential to minimize the adverse effects of radiation on normal tissue when used preventively.
In addition to transiently inhibiting cell-cycle progression and sterilizing those cells capable of proliferation, irradiation disturbs the homeostasis affected by endogenous mediators of intercellular communication (humoral component of tissue response to radiation). Changes in the mediator levels may modulate radiation effects either by assisting a return to normality (e.g., through a rise in H-type cell lineage-specific growth factors) or by aggravating the damage. The latter mode is illustrated with reports on changes in eicosanoid levels after irradiation and on results of empirical treatment of radiation injuries with anti-inflammatory drugs. Prodromal, acute and chronic effects of radiation are accompanied by excessive production of eicosanoids (prostaglandins, prostacycline, thromboxanes and leukotrienes). These endogenous mediators of inflammatory reactions may be responsible for the vasodilatation, vasoconstriction, increased microvascular permeability, thrombosis and chemotaxis observed after radiation exposure. Glucocorticoids inhibit eicosanoid synthesis primarily by interfering with phospholipase A2 whilst non-steroidal anti-inflammatory drugs prevent prostaglandin/thromboxane synthesis by inhibiting cyclooxygenase. When administered after irradiation on empirical grounds, drugs belonging to both groups tend to attenuate a range of prodromal, acute and chronic effects of radiation in man and animals.
U.S. Pat. No. 5,380,668 to Herron (Jan. 10, 1995), the contents of the entirety of which are incorporated by this reference, discloses, among other things, various compounds having the antigenic binding activity of hCG. The oligopeptides disclosed therein are disclosed generally for use in diagnostic methods. Various patents and patent applications to Gallo et al. (e.g., U.S. Pat. No. 5,677,275 (corresponding to WO 96/04008 A1), U.S. Pat. No. 5,877,148 (also corresponding to WO 96/04008 A1), WO 97/49721 A1, U.S. Pat. No. 6,319,504 (corresponding to WO 97/49373), U.S. Patent Application 2003/0049273 A1 (also corresponding to WO 97/49373), U.S. Pat. No. 5,968,513 (corresponding to WO 97/49418), U.S. Pat. No. 5,997,871 (corresponding to WO 97/49432), U.S. Pat. No. 6,620,416, U.S. Pat. No. 6,596,688, WO 01/11048 A2, WO 01/10907 A2, and U.S. Pat. No. 6,583,109) relate to various oligopeptides and their use in, among other things, “inhibiting HIV infection,” “treating or preventing HIV infection,” “treating or preventing cancer,” “treating or preventing a condition characterized by loss of body cell mass,” “treating or preventing a condition associated with pathological angiogenesis,” “treating or preventing hematopoietic deficiency,” “ex vivo gene therapy,” “expanding blood cells in vitro,” and/or “providing blood cells to a subject.” As described in PCT International Publication No. WO 03/029292 A2 (published Apr. 10, 2003), PCT International Publication No. WO 01/72831 A2 (published Oct. 4, 2001), and U.S. Patent Application Publications 20020064501 A1 (published May 30, 2002), 20030119720 A1 (published Jun. 26, 2003), 20030113733 A1 (published Jun. 19, 2003), and 20030166556 A1 (published Sep. 4, 2003), U.S. patent application Ser. No. 11/249,541, filed on Oct. 13, 2005, International Application No. PCT/EP2005/003707, filed on Apr. 8, 2005, U.S. patent application Ser. No. 10/821,256, filed on Apr. 8, 2004, U.S. patent application Ser. No. 10/262,522, filed on Sep. 30, 2002, International Application No. PCT/NL01/00259 (International Publication No. WO 01/72831 A2) filed Mar. 3, 2001, U.S. Pat. No. 6,844,315 and U.S. Pat. No. 6,921,751, the contents of all of which are incorporated by this reference, compositions containing some of the oligopeptides described herein have immunoregulatory activity useful in, for example, the treatment of sepsis and other disease states and conditions.
The current invention relates to the body's innate way of modulating important physiological processes and builds on insights reported in PCT International Publications WO 99/59617 and WO 01/72831 and PCT International Application PCT/NL02/00639, the contents of the entirety of all of which are incorporated herein by this reference. These applications describe small gene-regulatory peptides that are present in pregnant women and are derived from proteolytic breakdown of placental gonadotropins, such as hCG. These breakdown products are often only about two to six amino acids long and were shown to have unsurpassed immunological activity that is exerted by regulating expression of genes encoding inflammatory mediators such as cytokines. Surprisingly, it was found that breakdown of hCG provides a cascade of peptides that helps maintain a pregnant woman's immunological homeostasis. These peptides balance the immune system to assure that the mother stays immunologically sound while her fetus does not get prematurely rejected during pregnancy, but instead is safely carried until its time of birth.
Furthermore, the current invention relates to U.S. patent application Ser. No. 10/821,240, which provides methods for screening and identifying further small gene-regulatory peptides and using the results from such screens, for example, with peptides derived from a reference peptide. For example, peptides to be analyzed were derived from C-Reactive Protein (CRP) (e.g., human CRP), such peptides include, LTSL (SEQ ID NO:1), FVLS (SEQ ID NO:2), NMWD (SEQ ID NO:3), LCFL (SEQ ID NO:4), MWDF (SEQ ID NO:5), FSYA (SEQ ID NO:6), FWVD (SEQ ID NO:7), AFTV (SEQ ID NO:8), and WDFV (SEQ ID NO:9); peptides derived from Beta-catenin (e.g., human CTNB), such as GLLG (SEQ ID NO:10), TAPS (SEQ ID NO:11), VCQV (SEQ ID NO:12), CLWT (SEQ ID NO:13), VHQL (SEQ ID NO:14), GALH (SEQ ID NO:15), LGTL (SEQ ID NO:16), TLVQ (SEQ ID NO:17), QLLG (SEQ ID NO:18), YAIT (SEQ ID NO:19), LCEL (SEQ ID NO:20), GLIR (SEQ ID NO:21), APSL (SEQ ID NO:22), ITTL (SEQ ID NO:23), QALG (SEQ ID NO:24), HPPS (SEQ ID NO:25), GVLC (SEQ ID NO:26), LCPA (SEQ ID NO:27), LFYA (SEQ ID NO:28), NIMR (SEQ ID NO:29), NLIN (SEQ ID NO:30), LHPP (SEQ ID NO:31), LTEL (SEQ ID NO:32), SPIE (SEQ ID NO:33), VGGI (SEQ ID NO:34), QLLY (SEQ ID NO:35), LNTI (SEQ ID NO:36), LWTL (SEQ ID NO:37), LYSP (SEQ ID NO:38), YAMT (SEQ ID NO:39), LHNL (SEQ ID NO:40), TVLR (SEQ ID NO:41), and LFYA (SEQ ID NO:42); peptides derived from beta-hCG (e.g., human CG), such as GLLLLLLLS (SEQ ID NO:43), MGGTWA (SEQ ID NO:44), TWAS (SEQ ID NO:45), TLAVE (SEQ ID NO:46), RVLQ (SEQ ID NO:47), VCNYRDV (SEQ ID NO:48), FESI (SEQ ID NO:49), RLPG (SEQ ID NO:50), PRGV (SEQ ID NO:51), NPVVS (SEQ ID NO:52), YAVALS (SEQ ID NO:53), LTCDDP (SEQ ID NO:54), EMFQ (SEQ ID NO:55), PVVS (SEQ ID NO:56), VSYA (SEQ ID NO:57), GVLP (SEQ ID NO:58), FQGL (SEO ID NO:59), and AVAL (SEQ ID NO:60); peptides derived from Bruton's tyrosine kinase (e.g., human BTK), such as LSNI (SEQ ID NO:61), YVFS (SEQ ID NO:62), LYGV (SEQ ID NO:63), YVVC(SEQ ID NO:64), FIVR (SEQ ID NO:65), NILD (SEQ ID NO:66), TIMY (SEQ ID NO:67), LESI (SEQ ID NO:68), FLLT (SEQ ID NO:69), VFSP (SEQ ID NO:70), FILE (SEQ ID NO:71), TFLK (SEQ ID
NO:72), FWID (SEQ ID NO:73), MWEI (SEQ ID NO:74), QLLE (SEQ ID NO:75), PCFW (SEQ ID NO:76), VHKL (SEQ ID NO:77), LYGV (SEQ ID NO:63), LESI (SEQ ID NO:68), LSNI (SEQ ID NO:61), YVFS (SEQ ID NO:78), IYSL (SEQ ID NO:79), and NILD (SEQ ID NO:66); and peptides derived from matrix metalloproteinase-2 (e.g., human MM02), such as FKGA (SEQ ID NO:80), FFGL (SEQ ID NO:81), GIAQ (SEQ ID NO:82), LGCL (SEQ ID NO:83), YWIY (SEQ ID NO:84), AWNA (SEQ ID NO:85), ARGA (SEQ ID NO:86), PFRF (SEQ ID NO:87), APSP (SEQ ID NO:88), CLLS (SEQ ID NO:89), GLPQ (SEQ ID NO:90), TFWP (SEQ ID NO:91), AYYL (SEQ ID NO:92), FWPE (SEQ ID NO:93), CLLG (SEQ ID NO:94), FLWC (SEQ ID NO:95), RIIG (SEQ ID NO:96), WSDV (SEQ ID NO:97), PIIK (SEQ ID NO:98), GLPP (SEQ ID NO:99), RALC (SEQ ID NO:100), LNTF (SEQ ID NO:101), LSHA (SEQ ID NO:102), ATFW (SEQ ID NO:103), PSPI (SEQ ID NO:104), AHEF (SEQ ID NO:105), WRTV (SEQ ID NO:106), FVLK (SEQ ID NO:107), VQYL (SEQ ID, NO:108), KFFG (SEQ ID NO:109), FPFR (SEQ ID NO:110), IYSA (SEQ ID NO:111), and FDGI (SEQ ID NO:112), and others.